Thrombocytes or platelets function primarily in hemostasis. Increasingly, they have been implicated in cancer progression and metastasis via TGF?, VEGF, MMP-2, ATP and other mediators. Moreover, platelets can regulate innate immunity and inflammation by activating neutrophils via GPIb, p-selectin and TREM-I ligand. They have also been shown to activate dendritic cells (DCs) via a CD40L-CD40 pathway, and promote antigen cross-presentation through shuttling bacterial antigens to DCs. Surprisingly, however, the roles of platelets in anti-tumor immunity have received little attention in the field and are still undefined, despite anti-platelet agents appearing to be effective in preventing cancer progression in a number of large clinical studies. In particular, cancer-associated thrombocytosis correlates with the poor clinical outcome, but the underlying mechanism is unclear. A specific and important question is related to the role of platelets in shaping cancer-associated immunity via a multitude of molecules in the secretome of activated platelets (SAP). Our preliminary studies have demonstrated that SAP suppresses activation and effector function of both CD4 and CD8 T cells by a soluble factor that is stable and fractionable. Moreover, using our unique mouse model of thrombocytopenia due to the loss of gp96, an obligatory chaperone for the platelet GPIb-IX-V complex, we show that platelets significantly promote methylcholanthrene (MCA)-induced fibrosarcoma. Tumor development in the thrombocytopenic environment correlated significantly with the reduction of circulating myeloid-derived suppressor cells (MDSCs), more abundant tumor-infiltrating CD8 T cells, and increased T cell effector function. Finally, using an adoptive T cell transfer strategy, we found that thrombocytopenia promoted anti-melanoma immunity by CD8 T cells in vivo that correlated with the reduction of MDSCs. Our studies led us to hypothesize that platelets play negative and immunoregulatory roles in cancer immunosurveillance via promoting MDSCs and suppressing T cell activation and functionality. This novel hypothesis will be addressed by the four specific aims. Aim 1 will determine if platelets participate in cancer immune surveillance by answering if reduction of MCA-induced fibrosarcoma in PF4-gp96 KO mice is due to enhanced adaptive immunity. We will also determine if platelet defect enhances priming of tumor-specific immunity against multiple tumor systems. Aim 2 will use our promising biochemical strategy to define the molecular mechanism by which the platelet secretome blunts CD4 and CD8 T cell activation. Aim 3 will uncover the mechanism of platelet-MDSC cross-talk in the context of adoptive therapy of tumors with tumor-specific CD8 T cells. Our final aim will allow us to optimize a platelet- targeted strategy to enhance immunotherapy of melanoma. Collectively, our study will uncover underlying immune-based mechanisms by which thrombocytes promote cancer and it will solidify the idea of a combination of immunotherapy and anti-platelet agents as a novel and effective strategy against cancer.